Download Clinical Trials – The New Frontier of Cancer Treatment

Clinical Trials – The New Frontier of
Cancer Treatment
Dax Kurbegov, MD
Vice President, National Oncology Service Line, CHI
Principle Investigator, CHI Oncology Research Alliance NCORP
Saturday, April 11, 2015
The speaker has no financial or other
conflicts of interest to disclose…
But I’ll keep trying…
“The charm of history and its enigmatic lesson consist in the fact
that from age to age, nothing changes and yet everything is
completely different.”
- Aldous Huxley
Discussion Topics
A Brief History of the Clinical Trial
Clinical Trials 101 – Key Concepts
Cancer Clinical Trials: Today’s Landscape
New Clinical Trial Designs
A Brief History of the Clinical Trial
A Brief History of the Clinical Trial
Babylon – 562 BC
King Nebuchadnezzar
• Role of diet in human health
• Meat-rich v. legume-restricted
• First trial to guide a public
health decision
Collier R. Legumes, lemons and streptomycin: A short
history of the clinical trial. CMAJ : Canadian Medical
Association Journal 2009;180(1):23-24.
doi:10.1503/cmaj.081879.
A Brief History of the Clinical Trial
Persia – 1025 AD
Avicenna – Canon of Medicine
Set forth rules for drug testing:
•
•
•
•
•
•
•
Drug must be pure
Use for a “simple disease”
Test on at least 2 types of disease
Quality of drug related to strength
of disease
Timing of observations should rule
out natural healing
Drug effect must be reproducible
Animal trials should precede
human
Bhatt A. Evolution of Clinical Research: A History Before
and Beyond James Lind. Perspectives in Clinical Research
2010;1(1):6-10.
A Brief History of the Clinical Trial
Great Britain - 1747
James Lind – Father of the Clinical Trial
Treatise on Scurvy -1753
“They all in general had putrid gums,
the spots and lassitude, with weakness
of the knees.”
•
•
•
•
Isolation
Groups of 2
Six therapeutic interventions
Documentation
A Brief History of the Clinical Trial
1863 – United States
Austin Flint – A Treatise on the
Principles & Practice of Medicine
First utilization of a placebo
“The favorable progress of cases
was such as to secure for the
remedy generally the entire
confidence of the patients.”
A Brief History of the Clinical Trial
1946 – United Kingdom
Sir Austin Bradford Hill
Father of the Modern Clinical Trial
Streptomycin in Tubercolosis
• Meticulous trial design.
• Defined entry criteria and data
collection.
• First widely publicized trial to
incorporate randomization.
Clinical Trials 101 – Key Concepts
What is a Clinical Trial?
• Cancer clinical trials are research studies
conducted by medical scientists to
improve the care and treatment of
cancer patients
• Cancer clinical trials test ways to:
– Diagnose and treat cancer in people
– Prevent or reduce disease or
treatment side effects
– Prevent a recurrence of cancer
– Improve the comfort and quality
of life of people with cancer
– Understand non-medical factors that
impact outcomes for cancer patients
Drug Development
Early Phase Clinical Trials
Late Phase Clinical Trials
Continued Study
Traditional Clinical Trial Design
One Tumor Type, One Experimental Therapy, One Standard Therapy
Scenario 1
Randomization
Experimental
Drug
Experimental
therapy
Tumor Type 1
Standard
therapy
Scenario 2
Randomization
Experimental
Drug
Experimental
therapy
Target A
Standard
therapy
Randomization
Randomization is the process of assigning clinical trial
participants to treatment groups. Randomization gives each
participant a known (usually equal) chance of being assigned to
any of the groups. Successful randomization requires that group
assignment cannot be predicted in advance.
Why Randomize?
If, at the end of a clinical trial, a difference in outcomes occurs
between two treatment groups (say, intervention and control)
possible explanations for this difference would include:
 the intervention exhibits a real effect;
 the outcome difference is solely due to chance;
 there is a systematic difference (or bias) between the groups
due to factors other than the intervention.
Randomization aims to obviate the third possibility.
Clinical Trials: Myths and Misconceptions
FALSE
Clinical Trials: Myths and Misconceptions
FALSE
Clinical Trials: Myths and Misconceptions
FALSE
Clinical Trials: Myths and Misconceptions
TRUE & FALSE
Clinical Trials 101: Summary
Before making any treatment decisions,
ask questions and gather information.
The more information you have, the
easier it will be to make decisions and
manage challenges
Potential benefits of participation in clinical trials
• Receive, at minimum, the best treatment available
• Be among the first to benefit from a new treatment
• Receive a lot of attention and support, including close monitoring to
ensure safety
• Have access to doctors with extensive experience in the type of cancer
you have
Cancer Clinical Trials: Today’s Landscape
The Cancer Landscape in 2015
• 1.65 million new cases predicted
• Almost 600,000 cancer related deaths
• 5 year survival rate has improved from 49% in the 1970’s to
68% from 2003-2009
• 14.5 million survivors compared with 3 million survivors in
1971
• Novel therapies becoming the norm – recent FDA approvals
• Angiogenesis inhibitors – ramucirumab, sorafenib
• Antibodies – obinutuzumab
• Cell signaling inhibitors – dabrafenib, trametinib, idelalisib,
ceritinib
• Epigenome modifying agents - belinostat
AACR Progress Report 2014
A Revolution in Cancer Therapy
Genomics
Proteomics
Metabolomics
Immuno-oncology
The Promise of Precision Medicine
MacConaill LE, Garraway LA. J Clin Oncol 2010;28:5219-5228.
Problems with Current Trial Design
•
•
•
•
•
•
•
Classical phase I,II, and III models require enormous resources
Time to bring a new oncology drug to market 8-12 years
Cost to bring a new drug to market can exceed $1 billion
70% of oncology drugs fail in phase II
59% of oncology drugs fail in phase III
Have focused on histology-dependent strategies
Limited collaboration between sponsors, academia, and
funding sources
• Traditional models not designed to address “niche” agents
with very small populations expected to benefit
Kaitin, KI, Dimasi JA. Pharmaceutical Innovation in the 21st century:
new drug approvals in the first decade, 2000-2009. Clin Pharmacol
Ther 2011; 89: 183-188.
KolaI, Landis J. Can the pharmaceutical industry reduce attrition
rates? Nat Rev Drug Discov 2004 Aug; 3(8): 711-715.
Is There a Better Way?
In advanced breast cancer between 1998-2012:
14% of drugs in development were approved
23% of drugs in development approved when selecting for Her2 status
Selecting for Her2 associated with a 27% reduction in costs
In advanced non-small cell lung cancer between 1998-2012:
Biomarker targeted therapy was associated with a six-fold increase in trial success
Parker, JL et al. Breast Cancer Res Treat. 2012 Nov;136(1):179-85.
Falconi, A. et al. Journal of Thoracic Oncology: Feb 2014 - Volume 9 (2):
p 163–169
New Clinical Trial Designs
New Trial Designs
Methodologies
Major Goals
1.
1.
Biomarker guided design
1.
2.
2.
Basket trials
Umbrella trials
Adaptive Design
2.
3.
Shorten time to get drugs to
the patients who need them
Reduce costs
Increase the number of trial
participants getting the best
treatment
Basket Trials
One Molecular Abnormality Targeted Across Multiple Tumor Types
The Old Way - Three distinct trials
Driven by tumor
type
Experimental
Drug
Target A
Tumor Type 1
Experimental
Drug
Target A
Tumor Type 2
Experimental
Drug
Target A
Tumor Type 3
Basket Trials
One Molecular Abnormality Targeted Across Multiple Tumor Types
Simultaneous execution of multiple studies
Target Driven
Tumor Type 1
Experimental
Drug
Target A
Tumor Type 2
Tumor Type 3
Redig, A. and Pasi, JA. Basket Trials and the Evolution
of Clinical Trial Design in an Era of Genomic Medicine.
Journal of Clinical Oncology, Vol. 33, 2015
NCI Molecular Analysis for Therapy Choice
(NCI-MATCH)
NCI-MATCH – Distinctive Features
• Discovery Trial – to inform anticipated larger phase II/III studies
• Over 40 drugs pledged
• More than 15 pharmaceutical companies participating
• More than 20 single arm, phase II studies conducted in parallel
• Arms can be added or deleted without impacting other arms
Umbrella Studies
One tumor type, multiple molecular targets
Patients with a
defined tumor type
Molecular
characterization of
biopsy
Histology
&
Target Driven
Target A
Arm A1
Arm A2
Target B
Arm B1
Arm B2
Target C
Arm C1
Arm C2
Sleijfer, S et al. Designing
Transformative Clinical Trials in the
Cancer Genome Era. J Clin Oncol 31:
1834-1841.
Basket/Umbrella Trials Summary
• A response to the explosion of potentially actionable mutations in human
cancers.
• Resulting in an increase in public-private collaborations
• Promise efficiency in drug evaluation compared with traditional histologydriven sequential studies
• Appear optimally positioned to evaluate large effects of targeted agents
on relatively rare targets
• Can detect strong hints of activity in early phase studies if appropriately
designed
• Suggest of different types with shared molecular aberrations may be more
similar than tumors from same type lacking molecular features
• Most established in the Phase II setting with increasing exploration in
Phase III
Adaptive Trial Designs
Adaptive Trial Designs
Key Features
Planned modifications based on
accumulating data within a study
that does not undermine the
validity or integrity of the study.
Trial Procedures:
Eligibility
Study Dose
Endpoints
Treatment Duration
Response Evaluation Diagnostic Procedures
Statistical Procedures:
Randomization
Data Monitoring
Sample size
Statistical Analysis Plan
Chow, SC and Chang, M. Adaptive design methods in
clinical trials – a review. Orphanet Journal of Rare
Diseases 2008, 3:11
Adaptive Trial Designs
Key Features
1. All changes are pre-planned
2. Allows the trial to “learn” from early results
3. Can increase the proportion of patients getting the better
treatment
4. May shorten the time it takes to complete the trial
5. Can be very complex to manage
Adaptive Trial Designs
Adaptive Randomization
Adaptive Trial Designs
Adaptive Randomization
Adaptive Trial Designs in Action
Troxacitabine in Acute Myelogenous Leukemia
Standard Design
Idarubicin
+
Cytarabine
Randomize AML
Patients
Idarubicin
+
Troxacitabine
Troxacitabine
+
Cytarabine
Alternate Design
25 patients
Adaptive
randomization to
patients
learn,25updating
after every
patient
25 patients
Giles et al. Journal of Clinical
Oncology, 2003.
Adaptive Trial Designs in Action
Assign with higher probability to the better
performing treatment
Idarubicin
+
Cytarabine
Randomize AML
Patients
Idarubicin
+
Troxacitabine
This arm dropped after 24th patient
Troxacitabine
+
Cytarabine
Trial stopped after 34 patients
Giles et al. Journal of Clinical
Oncology, 2003.
Adaptive Trials in Action
Summary of Results – Complete Response by Day 50
Randomize AML
Patients
Idarubicin
+
Cytarabine
10/18 = 56%
Idarubicin
+
Troxacitabine
3/11 = 27%
Troxacitabine
+
Cytarabine
0/11 = 0%
Strengths of Bayesian Adaptive Trials
•
•
•
•
•
•
•
•
Potentially smaller trials
Potentially shorter trials
More accurate conclusions
Able to address more questions
Better treatment for patients in clinical trials
Greatest potential in multi-armed trials
Benefits limited but real in two-armed trials
Suited to the task of pairing molecular signatures to targeted
agents
Berry, DA. Adaptive Clinical Trials: The
Promise and the Caution. J Clin Oncol
29: 606-609.
The Promise of New Trial Design
Too good to be true?
Thank you.
Where to learn more
• If your doctor does not bring up clinical trials as a
treatment option, don’t hesitate to ask
• Speak with an LLS Information Specialist
• Use the free LLS-supported TrialCheck®, powered by
eviti® | Clinical Trials to find clinical trials near you through
the LLS website www.LLS.org/clinicaltrials
• Refer to LLS booklets and listen
to telephone/web education
programs on your diagnosis
and emerging therapies
NCI National Clinical Trials Network
50
Use the free LLS supported
TrialCheck® to find clinical trials
• www.LLS.org/clinicaltrials, click on
• TrialCheck® search tool*
– Assists user to identify clinical trials that meet eligibility criteria for a specific
patient
– Asks 11 simple questions about the patient
o Questions include zip code, disease diagnosis and stage, treatment history and
the patient’s age
o Most questions are optional, but providing information allows TrialCheck to
eliminate trials for which the patient is not eligible
– Once the search is complete, clinical trials are organized by location,
showing those closest to the patient first
– Allows you to save your search results
– Allows you to sign up to receive updates when a new trial has been added
to your search results
– LLS Information Specialists can help
o (800) 955-4572
*TrialCheck® powered by eviti® | Clinical Trials
NCI National Clinical Trials Network
51
Check out these LLS resources
•
•
•
•
•
•
•
•
•
•
•
•
www.LLS.org
Publications www.LLS.org/resourcecenter
Upcoming telephone/web education programs www.LLS.org/programs
Past telephone/web education programs www.LLS.org/pastprograms
Webcasts www.LLS.org/webcasts
TrialCheck www.LLS.org/clinicaltrials
Information Specialists [email protected]
Professionally facilitated Family Support Groups www.LLS.org/supportgroups
Professionally moderated online Chats www.LLS.org/chat
Peer-to-peer support www.LLS.org/firstconnection
Financial assistance www.LLS.org/finances
Your local chapter
For information and to order materials, contact an
LLS Information Specialist at (800) 955-4572
or visit www.LLS.org
NCI National Clinical Trials Network
52